Three-Week Versus 4-Week Schedule of nab-Paclitaxel in Patients With Metastatic Breast Cancer: A Randomized Phase II Study

Abstract Background This head-to-head study compared a 3-week versus 4-week schedule of nab-paclitaxel in patients with metastatic breast cancer (mBC). Methods Patients with HER2-negative mBC were enrolled and randomly assigned (1:1) to receive nab-paclitaxel for a 3-week schedule (125 mg/m2 on days 1 and 8) or a 4-week schedule (same dose on days 1, 8, and 15) until disease progression or treatment intolerance. Patients with intolerable toxicities were allowed to receive a maintenance regimen after benefiting from nab-paclitaxel. The primary endpoint was progression-free survival (PFS). Results Ninety-four patients were included in the analysis (n = 47 in each arm). A longer median PFS (mPFS) was observed in the 3-week versus the 4-week schedule in the overall population (not reached vs. 6.8 months; hazard ratio [HR] = 0.44; P = .029). Patients in the 2 arms had a similar overall survival (28.0 vs. 25.8 months), objective response rate (51.1% vs. 48.9%), and disease control rate (93.6% vs. 80.9%). The 3-week schedule was associated with a lower rate of toxicity-related treatment discontinuation (8.5% vs. 29.8%) and dose delays (6.4% vs. 23.4%). Conclusion This study demonstrated the better antitumor activity and safety profile of a 3-week over 4-week nab-paclitaxel schedule in HER2-negative mBC, suggesting that a 3-week schedule may be a better treatment regimen in clinical practice (ClinicalTrials.gov Identifier: NCT04192331).


Discussion
Taxanes are considered among the most active chemotherapy agents in the standard treatment paradigm for mBC. 1 However, conventional taxane-associated hypersensitivity reactions and neuropathy are significant challenges for clinicians and patients. 2nab-paclitaxel is a novel solvent-free formulation developed to overcome some of the problems associated with solvent-based paclitaxel and has been recommended widely for mBC.However, a higher dose of nabpaclitaxel qw3/4 (150 mg/m 2 ) is poorly tolerated, leading to dose reduction in at least 47% of patients. 3Therefore, optimizing dose schedules considering both favorable efficacy and tolerability profile remain an urgent need to improve patient compliance.
In summary, this study of HER2-negative mBC demonstrated a better efficacy and more favorable safety profile for the 3-week nab-paclitaxel schedule compared with the 4-week schedule.Author disclosures and references available online.

Study Procedures
Eligible patients were randomly assigned in a 1:1 ratio to 2 treatment arms: a 3-week regimen (125 mg/m 2 nab-paclitaxel on days 1 and 8 in a 21-day cycle) or a 4-week regimen (125 mg/ m 2 nab-paclitaxel on days 1, 8, and 15 in a 28-day cycle).nabpaclitaxel was administered intravenously, and the treatment cycle was decided by investigators according to the tumor response and tolerability.For patients with sustained tumor response and good tolerance, persistent treatment could be recommended.Patients with stable disease and poor tolerance were allowed to receive endocrine therapy or oral chemotherapy as maintenance treatment if they received over 6 cycles of chemotherapy.Because of the different administration schedules between the 2 arms, the patients and physicians were not blinded to treatment allocation.Dose reductions or delays were permitted in case of unacceptable toxicity.To avoid repeated hospital visits caused by AEs during the COVID-19 pandemic, most patients with poor bone marrow reserves were administered prophylactic colony stimulating factor (G-CSF) in the 2 arms.

Endpoints and Assessment
The primary endpoint was progression-free survival (PFS), the time from randomization to disease progression or death from any cause, whichever occurred first.The secondary endpoints included the objective response rate (ORR, defined as the proportion of patients with the best overall response of the complete response [CR] and partial response [PR]) as per RECIST version 1.1, disease control rate (DCR, defined as the proportion of patients with CR, PR, and stable disease [SD]), overall survival (OS, defined as the time from randomization to death from any cause), and safety.Radiologic assessment was performed by 2 independent investigators every 8 weeks during the treatment period, until disease progression, death, or consent withdrawal.The investigator assessed AEs were assessed and classified according to severity grade using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.

Statistical Analysis
The trial was powered to assess PFS between the 2 different dose schedules of nab-paclitaxel.Assuming an equal median PFS of 5 months, 4,5 a hazard ratio (HR) of 0.40 for the 3-week arm, an overall type I error of 2-sided 0.05, and a power of 80%, a total of approximately 37 progression events or deaths were required for the analysis.The study initially planned to randomly assign 94 patients (47 in each arm), assuming a 10% dropout rate.
Efficacy analyses were performed in the full analysis set (FAS) population who had received at least one dose of the study drug.For the primary analysis of PFS, data for patients who were alive and did not have disease progression, lost to follow up, or received non-study antitumor treatment before gaining evidence of objective tumor progression were censored to exclude the effects of maintenance therapy on PFS.To consider the impact of maintenance therapy in the sensitivity analysis of PFS, data from patients who were alive and did not have disease progression or who were lost to follow up were censored at the time of the last tumor assessment.For the analysis of OS, data from patients who were alive or lost to follow up were censored at the time of the last follow-up.The Kaplan-Meier method generated time-to-event curves, from which median values were calculated.A stratified log-rank test was used to compare the treatment groups, with an estimation of the HR and 95% CIs (CIs) from the log-rank test statistics.The relative dose intensity (RDI) was calculated as the actual dose intensity divided by the planned dose intensity during treatment.All statistical tests were 2-sided, with significance at P < .05.

assessmenT, analysis, anD DisCussion
Completion Study completed Investigator's assessment Active and should be pursued further Schedule modification is a common strategy in clinical oncology to optimize the therapeutic index of established cytotoxic agents.The present head-to-head randomized phase II study in HER2-negative mBC demonstrated a better efficacy and more favorable safety profile for the 3-week nab-paclitaxel schedule compared with the 4-week schedule, which should be recommended by guidelines in the future.
7][8] Here, we used a dose of 125 mg/m 2 qw2/3 because of its tolerability.This reduced dose is now widely accepted by many cancer centers in China 9 and other Asian countries. 10,11This study was the first prospective study to compare the 3-week versus 4-week dose of 125 mg/m 2 .In this randomized trial, we observed a PFS benefit for the 3-week schedule over the 4-week schedule in HER2-negative mBC after excluding the impact of maintenance therapy.Despite the fact that mPFS was not reached in the 3-week arm, the early mPFS benefit detected after the 6-cycle nab-paclitaxel treatment was maintained in the 3-week versus the 4-week schedule, as evidenced by the significant separation of the Kaplan-Meier curve at 6 months and the 24.7% increase in the 6-month PFS rate (78.0% vs. 53.3%).Although maintenance therapy contributed to additional events, the PFS benefit observed during the nabpaclitaxel therapy afforded by the 3-week regimen seemed to have been maintained through to the end of the study because the 3-week regimen afforded a numerical benefit in PFS with a 2-month extension compared with the 4-week regimen (8.5 vs. 6.5 months), although this difference was not significant.The observed survival benefit associated with the 3-week schedule may be attributed to better patient compliance, ie, the patients completed more cycles of treatment in the 3-week arm (the ≥6-cycle completion rate was 72.3% in this arm, which was far better than the 31.9%observed in the 4-week arm); as well as to the lower toxicity-related treatment discontinuation rate and reduced dose delays recorded in the 3-week arm.These results demonstrated that a more tolerable treatment schedule might allow for a favorable balance between efficacy and quality of life in patients with metastatic breast cancer.The greater probability of a better outcome in the 3-week schedule may be attributed to the fact that a 21-day interval of dose delivery is the best response window for tumor cells, because it matches the tumor cell repair cycle, thus achieving a better therapeutic effect. 12Moreover, this explains why a 3-week schedule is mostly considered the standard regimen for most chemotherapies.In turn, data on the efficacy of the qw2/3 regimen used in this study seems better than previously reported data from various q3w dose regimens, with a PFS ranging from 6.66 to 7.34 months. 13here was no OS benefit in the 3-week regimen compared with the 4-week arm, which might be attributed to the complex situation of the treatment of mBC.In addition, patient compliance, endocrine sensitivity, and subsequent maintenance treatments may affect OS to a large extent.Consistently, the ORR (51.1% vs. 48.9%)and DCR (93.6% vs. 80.9%) also exhibited no notable differences between the 2 arms.Our results were generally comparable with the data from a previous trial reported by Tamura et al, 14 in which nab-paclitaxel (as the first-line chemotherapy) achieved an ORR of 56.1% and a DCR of 92.9% in Asian patients with HER2-negative mBC.
The 3-week schedule was investigated in the hope of providing a better safety profile to the patients.Consistently, here, the 3-week schedule of nab-paclitaxel afforded a generally more favorable safety profile.Several AEs, including vomiting, blood bilirubin increase, and ≥grade 3 neutrophil count decrease, occurred more frequently in the 4-week arm.Notably, few dose reductions associated with nab-paclitaxel (2.1%-4.3%)occurred in the 2 arms, which was a better outcome than the data obtained from the 4-week schedule of 100-150 mg/m 2 nab-paclitaxel (~50%-70%). 3,7The prophylaxis for neutropenia administered during the COVID-19 pandemic might explain the fewer events of dose reduction observed in our study.The common AEs were similar to those of previous studies. 8,15Overall, with the goal of obtaining a favorable safety profile and better compliance combined with fewer hospital visits, the 3-week schedule is recommended with priority.
Several limitations of the present study should be recognized.First, this analysis was based on a small sample, which may have led to a hidden bias.Second, a small proportion of patients in the 2 arms had delayed treatment because of the COVID-19 pandemic, which might have affected the interpretation of the efficacy results.However, the calculated RDI data showed that the patients in 2 arms comparability received more than 80% of the planned dose intensities because of the prophylactic use of G-CSF, and this RDI level also ensured the anticipated efficacy well. 16,17Further confirmation of a better PFS and a comparison of long-term benefits remain necessary.
In summary, this study demonstrated the better safety profile and anti-cancer activity of the 3-week schedule of nabpaclitaxel compared with the 4-week schedule in patients with HER2-negative mBC.Because of the superiority in the patient adherence to the 3-week schedule, this might be a better regimen in clinical practice.The optimal nab-paclitaxel dose and dosing schedule remain an open question and should be confirmed in future studies.

Figure 2 .
figures anD Tables

Figure 3 . 12 e1299Figure 5 .
Figure 3. Efficacy outcomes of progression-free survival (PFS) as classified by the patients.(A) Kaplan-Meier survival curves of PFS demonstrating a similar result in first-line patients; (B) Kaplan-Meier survival curves of PFS demonstrating a better tendency in the 3-week arm versus the 4-week arm in second-or later-line patients (6.2 vs. 3.9 months).

Table 1 .
Baseline demographic and clinical characteristics.

Table 2 .
Treatment exposure and dose modifications.

Table 3 .
Summary of adverse events.